This application is a 371 of PCT/EP00/06562 Jul. 11, 2000.
The present invention relates to a novel process for preparing 2-aminomethyl-4-cyanothiazole.
The synthesis of 2-aminomethylthiazoles which contain a functional group such as a carboxylic acid, a carboxylic ester, a carboxamide or a carbothioamide in the 4-position has been described in the literature; literature (1): J.-L. Bemier, R. Houssin, J.-P. Henichart, Tetrahedron 42 (1986), 2695; literature (2): U. Schmidt et al., Synthesis (1987), 233; literature (3): G. Jung et al., Angew. Chem. Int. Ed. 35 (1996), 1503; literature (4): WO 9806741; literature (5): Kenner et al., J. Chem. Soc. (1963), 2143.
The abovementioned processes known from the literature have been described for small laboratory batches and are, for some reaction steps, not particularly suitable for a preparation on an industrial scale. For example, literature (2) describes the synthesis of the 4-ethoxycarbonylthiazole derivative using a Z protective group (Z=benzyloxycarbonyl). However, the Z protective group can, after conversion of the corresponding carboxamide into the Z-protected 2-aminomethyl4-cyanothiazole, no longer be removed by methods known from the literature (for example hydrogenolytically or with HBr) on an industrial scale with the cyano group remaining intact.
The 2-benzamidomethyl-4-ethoxycarbonylthiazole, which is described in literature (5), is, after further conversion into the corresponding benzoyl-protected 4-cyanothiazole, likewise unsuitable for removing the protective group with the cyano group remaining intact.
Literature (3) describes the synthesis of the 4-hydroxycarbonylthiazole derivative using the BOC protective group (BOC=tert-butyloxycarbonyl) which can be cleaved off with the cyano group remaining intact. However, a precursor of the thiazole derivative, i.e. the N-BOC-glycinethioamide, is synthesized from the BOC-glycinamide using Lawson""s reagent which, when used on an industrial scale, would involve considerably higher costs than the hydrogen sulfide method described in literature (2). Lawson""s reagent is also employed in literature (1).
The authors of literature (3) describe the cyclization to the 4-carboxylic acid of the thiazole using bromopyruvic acid. This route is also possible on an industrial scale; however, it has the disadvantage that bromopyruvic acid is less stable than ethyl bromopyruvate, which is used in literature (1), (2) and (5), and that the preparation of the thiazole carboxamide via the thiazole carboxylic acid involves higher technical expense. Moreover, it was not possible to achieve the thiazole carboxylic acid yield described in literature (3) on a larger scale when using CaCO3.
Using the procedure described in literature (1), the preparation of ethyl thiazole carboxylate with ethyl bromopyruvate in diethyl ether was very much incomplete. Instead of the stated reaction time of 3 h, our own studies showed that even after 20 h only some of the starting material (thioamide) had reacted. The desired ethyl thiazole carboxylate had indeed been formed in addition to a number of byproducts; however, in none of the experiments was it possible to even come close to the stated yield.
Likewise, it was not possible to employ the procedure, described in literature (2), for the cyclization to the thiazole carboxylic ester successfully. The use of ethanol at 65xc2x0 C. in the presence of molecular sieves resulted in rapid cleavage of the BOC protective group, owing to HBr being formed. Even at 40xc2x0 C. in ethanol and with other alcohols (for example methanol or isopropanol), it was not possible to realize the procedure of literature (2) with yields  greater than 70%. Addition of basic solution did likewise not lead to higher yields.
2-Aminomethyl-4-cyanothiazole would be an interesting intermediate for preparing serine protease-inhibiting low-molecular-weight substances (for example thrombin inhibitors), if it was readily available industrially. Such thrombin inhibitors are mentioned, for example, in WO 9806741. 2-Aminomethy-4-cyanothiazole can also be employed for preparing other thrombin inhibitors and prodrugs thereof, for example N-(ethoxycarbonyl-methylene)-(D)-cyclohexylalanyl-3,4-dehydroprolyl-[2-(4-hydroxyamidino)-thiazole]methylamide hydrochloride.
It is an object of the present invention to provide a process for preparing 2-aminomethy-4-yanothiazole, thus making available this synthesis building block for further syntheses, in a cost-effective manner.
We have found that this object is achieved by cyclizing the thioamide with the bromopyruvate without addition of bases and without addition of molecular sieves in alcohol at room temperature with a yield of almost 90%. The yield depends highly on the dilution of the starting materials in alcohol and reaches its maximum after a reaction time of about 5 h. The reaction in alcoholic solution is preferably carried out in a concentration range of less than 0.75 mol/l, based on thioamide (IV). Particular preference is given to a concentration of from more than 0.25 mol/l to 0.55 mol/l, based on IV. At concentrations of 1 mol/l, the reaction no longer proceeds with satisfactory yields. According to the invention, the reaction temperature is in the range from xe2x88x925xc2x0 C. to 40xc2x0 C., preferably in the range from 5xc2x0 C. to 30xc2x0 C. and in particular from 10xc2x0 C. to 25xc2x0 C. At 65xc2x0 C., as in literature (2), little BOC-protected thiazole carboxylic ester, if any, can be isolated after less than 5 h, even at a relatively high dilution. In the series of the alcohols, it was possible to obtain higher yields with isopropanol than with methanol. Small amounts of water do not negatively affect the cyclization, so that dehydrating agents such as molecular sieves can advantageously be dispensed with.
Also unexpected was the aminolysis of the thiazole carboxylic ester with aqueous ammonia to give the thiazole carboxamide. Reaction was observed only on addition of substantially more than two molar equivalents NH3. Preference is given to an excess of at least 5 molar equivalents NH3, in particular to values of at least 10 molar equivalents NH3. The solubilizer used can likewise be alcohol. However, in the series of the alcohols, yields with methanol were higher than with isopropanol.
Thiazole carboxylic ester can be obtained in crystalline form. To remove the solvent, it is necessary to scavenge the HBr formed using bases. Under pH control, it is possible to use dilute aqueous sodium hydroxide solution or else ammonia for this purpose. By hydrolyzing the ester with, for example, aqueous sodium hydroxide solution and subsequently adding acid in a pH-controlled manner, it is also possible to prepare the corresponding BOC-protected thiazole carboxylic acid in a simple manner and with good yields by this route.
For a synthesis on an industrial scale, it is advantageous to prepare the thiazole carboxamide without isolating the ester in a one-pot process. Starting with the thioamide, it is then possible to achieve a yield of  greater than 60% of crystalline amide with small technical expense.
The conversion into the 2-aminomethyl-4-cyanothiazole can then easily be effected by dehydration with, for example, trifluoroacetic anhydride and subsequent gentle removal of the BOC protective group.
The present invention relates to a process for preparing 2-aminomethyl-4-cyanothiazole and its salts of the formulae Ia and Ib, 
in which
n=1 or 2 and,
for n=1, X is chloride, bromide, triflate and hydrogen sulfate and,
for n=2, X is sulfate,
which can be carried out by introducing the tert-butyloxycarbonyl protective group (BOC) at the nitrogen of the aminoacetonitrile, subsequently adding hydrogen sulfide to the nitrile group, cyclizing this N-BOC-glycinethioamide with bromopyruvate according to Scheme A to give the corresponding thiazole-4-carboxylic ester and then the thiazole-4-carboxamide and finally the 4-cyanothiazole derivative.
Shown in Scheme A, an advantageous process which can easily be carried out on an industrial scale is described: 
The aminoacetonitrile II is commercially available as a salt (sulfate, hydrogen sulfate, chloride), or as a free base.
The intermediates III to VII are mentioned in the literature references (1) and (3) (V and VI in each case as the ethyl ester).
The 4-cyanothiazoles VIII and IX are novel.
According to this process, the intermediates III, VI and VII can be converted advantageously, without further work-up, into the respective subsequent product. The 4-cyanothiazole salt IX, which is embraced by the formula Ia, can be reacted under pH-controlled conditions with bases to give the salt-free form of the formula Ib.
The invention furthermore provides processes for preparing 2-aminomethyl-4-cyanothiazole and its salts of the formulae Ia and Ib 
in which
n=1 or 2 and,
for n=1, X is chloride, bromide, triflate and hydrogen sulfate and,
for n=2, X is sulfate. In the process according to the invention, the thioamide of the formula IV 
is stirred with a bromopyruvate of the formula V, 
in which R1 is branched or linear C1-4-alkyl in an alcohol R2OH in which R2 is branched or linear C1-8-alkyl, HOxe2x80x94CH2xe2x80x94CH2xe2x80x94, HOxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 or C1-4-alky-Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 at from 5xc2x0 C. to 40xc2x0 C. until the conversion of the thioamide IV is essentially complete.
Moreover, according to the invention the resulting thiazole carboxylic ester of the formula VI, 
in which R1 is branched or linear C1-4-alkyl can be stirred in an alcohol R2OH at from 0xc2x0 C. to 40xc2x0 C. with from 5 to 50 molar equivalents NH3 of an aqueous ammonia solution until the reaction has essentially gone to completion.
The process according to the above steps can be carried out without isolating the intermediate VI.
The thiazole carboxamide of the formula VII 
can be filtered off as a solid.
Furthermore, the amide VII can subsequently be dehydrated to the BOC-protected 4-cyanothiazole of the formula VIII 
and the BOC protective group can be removed.
Furthermore, the invention relates to a process for preparing the compound of the formula VI 
where the thioamide of the formula IV 
is stirred with a bromopyruvate of the formula V, 
in which R1 is branched or linear C1-4-alkyl in an alcohol R2OH in which R2 is branched or linear C1-8-alkyl, HOxe2x80x94CH2xe2x80x94CH2xe2x80x94, HOxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94 or C1-4-alky-Oxe2x80x94CH2xe2x80x94CH2xe2x80x94 at from 5xc2x0 C. to 40xc2x0 C. until the conversion of the thioamide IV has essentially gone to completion.
If appropriate, in the preparation of the compound of the formula VII 
according to the above process, the resulting thiazole carboxylic ester of the formula VI, 
in which R1 is branched or linear C1-4-alkyl is stirred in an alcohol R2OH at from 0xc2x0 C. to 40xc2x0 C. with from 5 to 50 molar equivalents NH3 of an aqueous ammonia solution until the conversion has essentially gone to completion.
Alternatively, the preparation of a compound of the formula VI 
is carried out by adding, after the conversion of the thioamide of the formula IV 
from 0.9 to 3 molar equivalents of a base, for example an amine, an alkali metal carbonate, alkali metal bicarbonate or alkali metal hydroxide, dissolved in water or undissolved, to the solvent and, after addition of water, if appropriate distilling off the solvent R2OH to the point where the ester VI begins to precipitate out, and bringing the precipitation, if appropriate, to completion by cooling the mixture and adding more water, and filtering off the thiazole carboxylic ester.
Furthermore, the reaction of the thioamide of the formula IV 
with the bromopyruvate of the formula V 
can be carried out in the solvent R2OH in which R2 is preferably C2-5-alkyl in the presence of from 1 to 3 molar equivalents of solid alkali metal bicarbonate, followed by work-up as described above.
Moreover, the process can be carried out by adding, in the preparation of a compound of the formula VII, 
after the conversion of the thioamide of the formula IV 
from 1 to 5 molar equivalents NH3 in the form of an aqueous ammonia solution to the solvent, distilling off from 30% to 60% of the alcohol R2OH in which R2 is preferably C15-alkyl, adding a further 5 to 50 molar equivalents NH3 in the form of aqueous ammonia and filtering off the resulting thiazole carboxamide precipitate, if appropriate after cooling the mixture.
Furthermore, the invention relates to compounds of the formulae Ia and Ib 
in which
n=1 or 2 and,
for n=1, X is chloride, bromide, triflate and hydrogen sulfate and,
for n=2, X is sulfate,
and to a compounds of the formula X 
in which R3 is a benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, trifluoromethylacetyl, acetyl or benzoyl radical. Preparation of the intermediates and the end product: